β-巯基氨基酸的合成与应用

doi:10.6023/cjoc202303023

摘要/Abstract

自然化学连接(Native chemical ligation, NCL)是蛋白质化学合成中里程碑式的重要反应. 在温和的中性水相缓冲液中, 通过自然化学连接可以将N端为半胱氨酸的多肽与C端为硫酯的多肽连接合成带有修饰的蛋白质. 天然蛋白质的半胱氨酸丰度仅为1.7%, 导致难以找到合适的半胱氨酸反应位点, 阻碍了NCL的广泛应用. “自然化学连接-脱硫”的策略首次将连接位点拓展到丙氨酸, 启发了化学家们通过不同类型的β-巯基氨基酸来介导NCL反应, 随后通过脱硫反应可以得到天然多肽序列, 为蛋白质的合成提供更多选择. 近年来, 多个课题组完成了β-巯基苯丙氨酸、亮氨酸、精氨酸、天冬氨酸、天冬酰胺、赖氨酸、甲硫氨酸、色氨酸、谷氨酸和谷氨酰胺的合成, 并应用NCL-脱硫策略合成蛋白质. 将对上述β-巯基氨基酸合成与应用予以综述.

关键词: 自然化学连接, β-巯基氨基酸, 脱硫

Native chemical ligation (NCL) is a milestone reaction in protein chemical synthesis. The NCL involves a reaction between an unprotected peptide with C-terminal thioester and a second unprotected peptide with N-terminal cysteine, which could give a new peptide in a neutral aqueous buffer solution. The cysteine abundance of natural proteins is only 1.7%, which makes it difficult to find suitable cysteine reaction sites and hinders the widespread application of NCL. The “NCL-desulfuri- zation” strategy extended the ligation site to alanine, inspiring chemists to mediate NCL reactions through different types of β-thiolated amino acids. After the NCL is completed, native peptide can be obtained through desulfurization reactions. The “NCL-desulfurization” provides more options for protein synthesis. In recent years, several research groups have completed the synthesis of β-thiolated phenylalanine, leucine, arginine, aspartic acid, asparagine, lysine, methionine, tryptophan, glutamic acid and glutamine, and applied NCL-desulfurization strategy to synthesize proteins. In this article, the synthesis and application of the above β-thiolated amino acids are reviewed.

Key words: native chemical ligation (NCL), β-thiolated amino acids, desulfurization

引用此文

上官豪若, 黄平, 戴振亚, 王平. β-巯基氨基酸的合成与应用[J]. 有机化学, 2023, 43(9): 3089-3097.

Haoruo Shangguan, Ping Huang, Zhenya Dai, Ping Wang. Synthesis and Application of β-Thiolated Amino Acids[J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3089-3097.

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图/表 13

图式1. 自然化学连接-脱硫反应

Scheme 1. Reaction of NCL-desulfurization

图式2. β-巯基苯丙氨酸7的合成

Scheme 2. Synthesis of β-thiolated phenylalanine 7

图式3. β-巯基苯丙氨酸13的合成

Scheme 3. Synthesis of β-thiolated phenylalanine 13

图式4. β-巯基亮氨酸20的合成

Scheme 4. Synthesis of β-thiolated leucine 20

图式5. β-巯基亮氨酸27的合成

Scheme 5. Synthesis of β-thiolated leucine 27

图式6. β-巯基精氨酸37的合成

Scheme 6. Synthesis of β-thiolated arginine 37

图式7. β-巯基天冬氨酸44的合成

Scheme 7. Synthesis of β-thiolated asparticacid 44

图式8. β-巯基天冬氨酸52的合成

Scheme 8. Synthesis of β-thiolated asparticacid 52

图式9. β-巯基天冬酰胺59和60的合成

Scheme 9. Synthesis of β-thiolated asparagine 59 and 60

图式10. β-巯基赖氨酸67和68的合成

Scheme 10. Synthesis of β-thiolated lysine 67 and 68

图式11. 光催化的Giese反应机理

Scheme 11. Mechanism of photocatalyis Giese reaction

图式12. 不同类型的β-巯基氨基酸

Scheme 12. Different types of β-thiolated amino acids

图式13. β-巯基芳基氨基酸的合成

Scheme 13. Synthesis of β-thiolated aryl amino acids

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